Annual Report of Cosmetology vol.9, 2001
Synopsis of Original Research Paper

Studies on the developmental processes of human cornified
cell envelope and the pathogenesis of its dysfunction
Masashi Akiyama
Department of Dermatology, Teikyo University School of Medicine, Ichihara Hospital

Terminally differentiated stratified squamous epithelium forms a lining of the plasma membrane
called the cornified cell envelope (CCE), a thick layer of several covalently cross-linked precursor
proteins including involucrin, small proline-rich proteins (SPRPs) and loricrin. Their cross-linkingisodipeptide bonds are formed by epidermal transglutaminases (TGases) 1, 2 and 3. The formationof CCE and sequential expression of major CCE precursor proteins, TGases, and 25-kD lamellar
granule-associated protein (LGP) were studied in human embryonic and fetal skin. Ultrastructurally,
membrane thickening has already started in periderm cells of the two-layered epidermis and anelectron dense, thickened cell envelope similar to CCE in adult epidermis is observed in periderm
cells at the three-layered and later stages of skin development. In the two-layered epidermis (4965 days EGA), immunoreactivities of involucrin, SPRPs, all the TGases and LGP were present onlyin the periderm. In the three-layered epidermis and thereafter (66-160 days EGA), loricrin became
positive in the periderm cells, TGases extended to the entire epidermis, and LGP was detected inintermediate cells as well as periderm cells. Immunoelectron microscopy demonstrated that all
three major CCE precursor proteins, involucrin, SPRPs and loricrin, were restricted to the CCE inperiderm cells at this stage of development. After 160 days EGA, the periderm had disappearedand CCE proteins and LGP were expressed in the spinous, granular and cornified cells and TGases
were detected in the entire epidermis. These findings indicate that CCE precursor proteins, TGases,and LGP are expressed in coordination in periderm cells during human epidermal development andsuggest that periderm cells form CCE in the process of regression.
As a next step, five patients with non-bullous congenital ichthyosiform erythroderma (NBCIE),
one patient with lamellar icthyosis and two patients with mutilating palmoplantar keratoderma(MPPK) were studied.
In one patient out of five NBCIE cases, expression of TGase 1 molecule was markedly reducedin the patient’s epidermis. Electron microscopy revealed incomplete thickening of CCE duringkeratinization in the epidermis. Sequencing of the entire exons and exon-intron borders of TGase
1 gene (TGM1) revealed that the proband was a compound heterozygote for two novel mutations,
9008delA and R388H. These findings indicate that the compound heterozygote for missense
mutation (R388H) in the core domain and the frameshift mutation (9008delA) resulting in apremature termination codon at the tail of the TGase 1 peptide leads to the NBCIE phenotype.
TGM1 mutations were also found in the lamellar ichthyosis patient.
In the patients with MPPK, ultrastructural, immunohistochemical, and immunoelectron microscopic
analyses revealed malformed CCE and reduced deposition of loricrin to CCE. Sequencing of theentire exons and exon-intron borders of loricrin gene of the patients excluded a mutation in loricrin
DNA sequence. These data confirm the presence of MPPK phenotype with abnormal loricrin
cross-linking at the final stage of CCE formation that is not caused by mutations in the epidermal
differentiation complex region.

The Cosmetology Research Foundation
http://cosmetology.or.jp/en/

Nichitoha-Hatchobori bldg. 5F, 3-11-8 Hatchobori, Chuo-ku, Tokyo 104-0032, Tokyo